Serotonin 1A receptors in the living brain of Alzheimer's disease patients

Abstract

4-[F-18]fluoro-N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)benzamide, a selective serotonin 1A (5-HT(1A)) molecular imaging probe, was used in conjunction with positron emission tomography (PET) for quantification of 5-HT(1A) receptor densities in the living brains of Alzheimer's disease patients (ADs) (n = 8), subjects with mild cognitive impairment (n = 6), and controls (n = 5). ADs had receptor densities significantly decreased in both hippocampi (binding potential: controls 1.62 +/- 0.07; ADs 1.18 +/- 0.26) and also in raphe nuclei (controls 0.63 +/- 0.09; ADs 0.37 +/- 0.20). When volume losses are included, 5-HT(1A) losses are even more severe (i.e., average mean decreases of 24% in mild cognitive impairment patients and 49% in ADs). A strong correlation of 5-HT(1A) receptor decreases in hippocampus with worsening of clinical symptoms (Mini Mental State Exam scores) was also found. Moreover, these decreases in 5-HT(1A) receptor measures correlate with decreased glucose utilization as measured with 2-deoxy-2-[F-18]fluoro-d-glucose PET in the brains of ADs (standardized uptake values; globally: controls 0.89 +/- 0.04, ADs 0.72 +/- 0.04; posterior cingulate gyrus: controls 1.05 +/- 0.09, ADs 0.79 +/- 0.11). They also inversely correlate with increased neuropathological loads measured with 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile PET in several neocortical regions in the same subjects. The in vivo observations were confirmed independently by in vitro digital autoradiography with 4-[F-18]fluoro-N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)benzamide and 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}-ethylidene)malononitrile on brain tissue specimens from two ADs and three nondemented subjects.

Figures

Fig. 1.

Group distribution of [F-18]MPPF hippocampus BP values (A), [F-18]MPPF hippocampus BPT values (B), and hippocampus volume values (C) for controls (blue), MCIs (yellow), and ADs (red). Hippocampus volumes are given in cm3; in all three cases, controls are statistically significantly separated from MCIs (P < 0.05) and from ADs (P < 0.001).

Fig. 2.

Scatter plots showing correlation between hippocampus volume and hippocampus [F-18]MPPF BP (A; rS = 0.76, P = 0.0002), and between hippocampus volume and hippocampus [F-18]MPPF BPT (B; rS = 0.95, P < 0.0001) for controls (blue), MCIs (yellow), and ADs (red); hippocampus volume is given in cm3.

Fig. 3.

Scatter plots correlating hippocampus [F-18]MPPF BPT with cognitive performance scores (MMSE scores) (A; rS = 0.67, P = 0.0015) and hippocampus [F-18]MPPF BP with MMSE scores (B; rS = 0.82, P < 0.0001); hippocampus [F-18]MPPF BPT values correlation with [F-18]FDG uptake measures: PCG SUVR (C; rS = 0.73, P = 0.0004) and MTL SUVR (D; rS = 0.81, P < 0.0001); and hippocampus [F-18]MPPF BPT with [F-18]FDDNP binding measures: PCG DVR (E; rS = –0.71, P = 0.0007) and MTL DVR (F; rS = –0.61, P = 0.006). Blue, controls; yellow, MCIs; red, ADs. The outlier AD case (*) is the presenilin-2 mutation patient.

Fig. 4.

Representative examples of brain PET transverse images from a control subject (Left), an MCI subject (Center), and an AD patient (Right): [F-18]MPPF BP (Top), summed (30–60 min) [F-18]FDG (Middle), and [F-18]FDDNP DVR (Bottom); the images from the AD patient show a strongly decreased level of [F-18]MPPF binding in hippocampus (arrows in Top) coinciding with globally decreased [F-18]FDG uptake in neocortical regions (e.g., parietal lobe; arrows in Middle) and increased levels of [F-18]FDDNP binding in cortical areas (e.g., in PCG; arrows in Bottom). Absolute scales are comparable within subjects with a specific probe. Warmer colors represent higher values.